Co-corresponding author and designer of cover layout for January 23, 2014 issue of Molecular Cell:

Research Interests

The Reiner lab research is divided into two general areas: mechanisms of cell signaling and harnessing model genetic organisms for drug discovery and translational biology.

Many oncogenes and tumor suppressor genes regulate signaling cascades that determine cell fate, proliferation, invasion, metastasis and other aspects of tumorigenesis. Traditionally such cascades are known as “pathways,” in large part due to a) the legacy of mostly linear (or so we thought at the time) biosynthetic pathways, and b) the essential nature of many core cascade components in evolutionarily diverse experimental organisms. However, diverse lines of reasoning argue that parallel signaling “pathways” are actually linked together as signaling networks to either work in concert or opposition to evoke a novel outcome. Furthermore, network plasticity is dynamically and spatiotemporally regulated during development, and probably tumorigenesis, to utilize divergent cascade effectors or partners to enact wildly dissimilar biological outcomes. We hypothesize that the notorious heterogeneity between and within cancer types with similar mutational profiles, both in cascade activation and pharmacological response, is a reflection of different tumor evolutionary clades utilizing diverse signaling partners.

We seek to identify novel network nodal points and dissect the mechanisms by which dynamic signal changes are regulated. Our system is the developing vulva of the nematode worm C. elegans, a classic genetic model organism. Most mammalian tumors arise from epithelial cells that are responding to extracellular growth factor signals. The vulva, a specialized epithelial tube, is similarly derived from an epithelial group responding to Epidermal Growth Factor (EGF) and the EGF receptor, and further patterned by Notch signaling. Each of six vulval precursor cells assumes the correct developmental fate with high fidelity. We found that the C. elegans ortholog of the small GTPase Ras, the most mutated oncoprotein in humans, dynamically switches signaling partners during vulval development, from the canonical Raf kinase to the RalGEF guanine nucleotide exchange factor that promotes Ral small GTPase signaling. Furthermore, these two effectors promote opposite and competing cell fates. Both Ras effectors are of critical importance in various human cancers. Our work provided the molecular mechanism to reconcile a long-standing conflict in the field, which was a proposed dual signaling of EGF to promote competing cell fates. We have extended this project to 1) show that RalGEF orchestrates two antagonistic cascades, Ral and PI3 Kinase, to fine-tune vulval developmental patterning, and 2) to characterize a Ral signaling cascade, a component of which may also orchestrate opposing signaling activities. Thus, a major theme of our research is signaling duality, a counterintuitive process by which the same protein can promote antagonistic outcomes. Our data suggest that signaling duality is a mechanistic underpinning of the emergent network property of exceptional developmental fidelity. Traditionally we think of DNA damage repair or cell cycle checkpoints as processes that impose informational or developmental fidelity, but we propose that signaling duality similarly enforces fidelity, perhaps in a way that prevents ambiguous cell fates that could subsequently lead to cancer.

A recent extension of this research, and a major new research focus, is our novel finding that Ral activates the central regulator of biosynthesis, metabolism, lifespan, diabetes, cancer, neurodegeneration, etc., TOR (Target of Rapamycin). We are excited to extend this finding into mechanistic analysis of TOR signaling.

The other general focus of the Reiner lab is to harness the power of C. elegans genetics to engineer animals for highly sensitized drug discovery screens. Here in the IBT Center for Translational Cancer Research on the 9th floor of the Alkek building is the John S. Dunn High Throughput Screening Core Facility, part of the Gulf Coast Consortia for Quantitative Biomedical Sciences. With them we are working to define a novel cross-platform drug discovery pipeline, with model organism small molecule inhibitor identification generating candidates for cell culture and mouse validation, and from there into the clinic. Consequently, our efforts are inherently collaborative. A key element of our project design is that, unlike conventional targeted drug therapy paradigms, we do not assume that we know the best target in a given system. Rather, we sensitize a system with a known mutation as an entry point for high throughput small molecule screening for specific phenotypic endpoints. We reason that the target identification can come later; we are looking for potentially valuable inhibitors in a given system regardless of the target, thereby complementing existing drug discovery paradigms. We began with oncogenic Rac and Ras as proofs of principle, and will extend to other entry points. We emphasize that in the long term our drug discovery scheme is generalizable: to other diseases with highly conserved molecular entry points (channelopathies, neurodegeneration, dystrophies, etc., as well as oncogenes) and to other model system platforms (yeast, worms, flies, frogs and fish).